Medical composition kit for treating lesioned abnormal tissue

ABSTRACT

Optimum compounding composition of a local injection preparation for treating rectal submucous lesioned abnormal tissue with local anesthetic is decided to provide a medical composition kit. In a composition kit for the treatment where respective containers are unsealed upon being used and respective contents are mixed to obtain a preparation for injection, a medical composition kit which is characterized in that respective single doses of a therapeutic preparation and local anesthetic are fractionally charged in containers, the said therapeutic preparation contains 1˜10% of a water-soluble aluminum compound and 0.01˜2% of tannic acid and the said local anesthetic contains 0.1˜1% of lidocaine hydrochloride or 0.5˜5% of procaine hydrochloride.

TECHNICAL FIELD

[0001] The present invention relates to a medical composition kit of a local injection preparation for treating rectal submucous lesioned abnormal tissue such as hemorrhoid and, more particularly, it relates to a medical composition kit comprising a local injection preparation for treating rectal submucous lesioned abnormal tissue containing a water-soluble aluminum compound and tannic acid and a local anesthetic for treating the same.

BACKGROUND ART

[0002] Treatment of internal hemorrhoid by injection has a history of not shorter than 100 years and, with regard to a composition, a ferric sulfate solution or a solution of phenol in olive oil was used in early years. After that, alcohol, kinin hydrochloride, mercury chloride, urethane, ergot, etc. had been used. In recent 30 years, a solution of phenol in vegetable oil, a solution of alum, etc. have been mainly used.

[0003] However, those compositions, the following problems for curing the internal hemorrhoid have not been well solved. Thus, in a sclerosing treating method for hemorrhoid by injection preparations, it is demanded that fibrogenesis of hemorrhoid tissue is finished with stopping the bleeding, inhibiting the growth microbes and remaining no hard nodule or causing no necrosis. However, the injection preparations up to now do not satisfy all of or most of those demands. Further, in injection preparations used in clinic fields, it is difficult to decide appropriate concentration and amount and also to decide a method for sclerosing the internal hemorrhoid without causing necrosis of the tissue. When the above-mentioned composition is injected, the site where the medicament is concentrated is limited to the submucous tissue only and, therefore, the injected site is to be expanded and the administration method is to be improved as well.

[0004] With regard to a composition for the treatment of hemorrhoid, there has been proposed an injection preparation comprising tannin, alum for medical use, sodium citrate, dextran, glycerol and trichlorobutyl alcohol (Journal of Traditional Chinese Medicine, 1(2), 115-120 (1981)). Chemical name for alum is aluminum potassium sulfate which is colorless and transparent octahedral crystal and has been known to have local astringent, hemostatic and antiseptic actions. However, even when this alum is taken per os, it is not absorbed from mucous membranes of stomach and intestine but merely shows a local action to mucous membrane. On the other hand, tannic acid is usually obtained from nutgall or gallnut and is a yellowish white to pale brown amorphous powder or small leaves or sponge-like bulk. Tannic acid has been known to coagulate protein in acidic or neutral solution, to show an astringent action and to have antiseptic and antibacterial actions.

[0005] Since the above-mentioned injection preparation uses trichlorobutyl alcohol, there is a probability of causing the following problems. Thus, trichlorobutyl alcohol is a bonded product of carbon with chlorine and produces a radical by absorption of light to oxide tannic acid whereupon tannic acid turns brown or black color to form a precipitate. Trichlorobutyl alcohol also has a property that, when strong energy (such as heat or light) is applied thereto, the bond is cleaved to change to unstable substance. It is not appropriate to use trichlorobutyl alcohol having such properties for pharmaceuticals and there is an inconvenience that an injection preparation comprising such a composition has much possibility of forming a precipitate during preservation and that preservation should be conducted with utmost carefulness.

[0006] In the Japanese Patent Laid-Open No. 04/225,920, there is disclosed a sclerosing agent for lesioned abnormal tissue of digestive organs in which a traditional plant medicine extract containing phenol compound, flavone or flavonoid, catechin compound or polycarboxylic acid is contained as a stabilizer in a composition where aluminum potassium sulfate and tannic acid are compounded as a medicament for sclerosing the lesioned abnormal tissue of digestive organs such as esophageal varix, hemorrhoid, rectal full-thickness prolapse, rectal mucosa prolapse and intestinal or rectal protrude lesioned tissue. However, since an extract of traditional plant medicines is contained in the composition as a stabilizer, it is very difficult to prepare a stabilizer having a predetermined composition and, even after troublesome extracting and purifying steps, there is still a risk that small amount of unidentified component is contaminated and that is a problem in terms of a pharmaceutical preparation. Further, even when an extract of traditional plant medicines is contained as a stablizer, a composition where aluminum potassium sulfate and tannic acid are compounded may be colored or, in some cases, precipitated when it is preserved for a long period in a state of an aqueous solution and that is a problem as a pharmaceutical preparation for injection.

[0007] In WO 94/06443 (International Laid-Open Date: Mar. 31, 1994), there is described an injection preparation for the treatment of lesioned abnormal tissue comprising 0.01˜0.5 molar concentration of a water-soluble aluminum compound, 0.5%˜25.0% (to the above water-soluble aluminum compound) of tannic acid, sodium hydrogen sulfite and polyhydric alcohol or saccharide having a pH of 1.5˜3.5. However, in a method for the manufacture of the said composition mentioned in the said patent, all constituting components for the composition are just dissolved at the same time or randomly. Thus, the method for the manufacture of the injection preparation mentioned in the said patent is constituted in such a manner that all components are placed in a test tube, water for injection is added thereto with stirring until a predetermined amount is resulted, the resulting aqueous solution is placed in a container such as glass bottle, oxygen dissolved in the solution is removed, the container is substituted with nitrogen gas, a high-pressure steam sterilization is carried out and the product is preserved in a cool place. However, it was found that, in the general method for the manufacture of injection solution described in the said patent as such, it is difficult to prepare a composition having a constant composition which is stable in terms of the pharmaceutical preparation whereby there is a problem to practically manufacture such a composition.

[0008] Aluminum potassium sulfate (alum) used as one of the components for the composition of the present invention has been used as a hemostatic agent while, in the Commentary for the Japanese Pharmacopoeia, there is mentioned that its use as a pharmaceutical by mixing with tannic acid is prohibited or, in other words, to be incompatible. However, although it has been attempted, as mentioned already, to mix both and to use as a pharmaceutical, when they are just mixed as they are, coloration is resulted and precipitation is generated whereby the product is extremely unstable. Use of such an unstable composition as an injection preparation is not adequate and, in addition, that is a problem in view of safety.

[0009] Aluminum potassium sulfate usually contains iron which is derived from bauxite used as a material. Therefore, in the Japanese Pharmacopoeia, the allowable amount of iron when used as a medical material for aluminum potassium sulfate is regulated to be 20 ppm or less. Further, aluminum potassium sulfate is dissociated in a solution to generate aluminum ions such as Al³⁺, Al(OH)²⁺ and Al(OH)₂ ⁺ and they react with hydroxyl ion OH to produce aluminum hydroxide Al(OH)₃ resulting in a precipitate in a solution. When a precipitate is produced in a solution as such, that is disqualified as a preparation for injection for treatment whereby it is naturally unusable for treatment.

[0010] On the other hand, tannic acid is oxidized by contacting with oxygen in air or with dissolved oxygen in the solution to give oxides such as quinone compounds resulting in a precipitate in the injection preparation. When such an insoluble products are precipitated in an injection preparation, it goes without saying that such a solution is disqualified as an injection preparation. Further, air oxidation of tannic acid is promoted to give a precipitate as an oxide especially when iron coexists in the solution. Accordingly, when tannic acid and aluminum potassium sulfate coexist in a solution, there is iron ion derived from aluminum potassium sulfate in the solution as mentioned already whereby the said iron ion directly reacts with tannic acid to form a precipitate and, at the same time, air oxidation is promoted. Furthermore, when aluminum ion exists in a solution, tannic acid directly reacts with the said aluminum ion to form a precipitate whereby it is apt to be subjected to air oxidation. Accordingly, when the components are merely compounded, it is never possible to manufacture a solution containing tannic acid and aluminum potassium sulfate in such a state that no precipitate is formed and that the composition is constant and is stable.

[0011] In order to solve the above, there has been already disclosed to manufacture an injection preparation having a constant and stable composition which is a composition for treating lesioned abnormal tissue such as hemorrhage by a full consideration of dissolving order, dissolving condition, etc. of the components (Japanese Patent Laid-Open No. 08/92,106).

DISCLOSURE OF THE INVENTION

[0012] A local injection preparation for treating rectal submucous lesioned abnormal tissue such as hemorrhoid is usually administered under rectal mucosa which is believed to have no sense of pain although sense of discomfort at anus or pain in which vagus nerve is believed to be participated sometime happens. Therefore, as a means for mitigating the local pain or sense of discomfort at anus of the patient, joint use with local anesthetic is usually carried out. However, such a use has a possibility of affecting the treating effect and safety of a water-soluble aluminum compound and tannic acid and also has a possibility of incompatibility. Therefore, doses of the water-soluble aluminum compound and tannic acid and selection and dose of local anesthetic are to be decided by taking the relation with the fate of a drug and pharmacological effect of the water-soluble aluminum compound and tannic acid into consideration. The matter that the present invention is to solve is that a study for an interaction of a local injection preparation for treating rectal submucous lesioned abnormal tissue with local anesthetic is carried out whereby the optimum utilizing means is determined.

[0013] The present inventors have carried out investigations whether local anesthetic affects the efficacy and safety of water-soluble aluminum compound and tannic acid when a local injection preparation for treating rectal submucous lesioned abnormal tissue containing water-soluble aluminum compound and tannic acid is used together with local anesthetic. For such a purpose, investigations on selection and compounding ratio of use of the local anesthetic were carried out to action of incarnation (index for sclerosis of tissue) and drug fate of aluminum and it has been found that local anesthetic can be used jointly without affecting the efficacy of water-soluble aluminum compound and tannic acid by merely utilizing a very specific means. It has been further found that, when they are previously made into a medical composition kit, precision of their compounding ratio can be maintained and, to be specific, troublesomeness in the treatment by medical doctors can be avoided by resulting in much convenience whereupon the present invention has been accomplished.

[0014] Thus, the present invention comprises:

[0015] (1) In a composition kit for the treatment where respective containers are unsealed upon being used and respective contents are mixed to obtain a preparation for injection, a medical composition kit for treating rectal submucous lesioned abnormal tissue which is characterized in that respective single doses of a therapeutic preparation and local anesthetic are fractionally charged in containers, the said therapeutic preparation contains 1˜10% of a water-soluble aluminum compound and 0.01˜2% of tannic acid and the said local anesthetic contains 0.1˜1% of lidocaine hydrochloride.

[0016] (2) In a composition kit for the treatment where respective containers are unsealed upon being used and respective contents are mixed to obtain a preparation for injection, a medical composition kit for treating rectal submucous lesioned abnormal tissue which is characterized in that respective single doses of a therapeutic preparation and local anesthetic are fractionally charged in containers, the said therapeutic preparation contains 1˜10% of a water-soluble aluminum compound and 0.01˜2% of tannic acid and the said local anesthetic contains 0.5˜5% of procaine hydrochloride.

[0017] (3) The medical composition kit for treating rectal submucous lesioned abnormal tissue according to the above-mentioned (1) or (2), wherein the water-soluble aluminum compound, tannic acid and lidocaine hydrochloride or procaine hydrochloride are previously and fractionally charged so that the final concentrations of them in the final preparation prepared as an injection preparation by mixing them are made 1.5˜2.5%, 0.01˜0.1% and 0.05˜0.5% or 0.1˜1%, respectively.

[0018] (4) The medical composition kit for treating rectal submucous lesioned abnormal tissue according to the above-mentioned (3), wherein pH of the preparation for the treatment is 2˜3.

[0019] (5) The medical composition kit for treating rectal submucous lesioned abnormal tissue according to the above-mentioned (3), wherein the water-soluble aluminum compound is aluminum potassium sulfate.

[0020] (6) The medical composition kit for treating rectal submucous lesioned abnormal tissue according to the above-mentioned (3), wherein the preparation for the treatment contains a chelating agent and an additive for stabilization.

[0021] (7) The medical composition kit for treating rectal submucous lesioned abnormal tissue according to the above-mentioned (6), wherein the final preparation where each component is mixed to give an injection preparation is prepared so as to contain 0.5˜1% of sodium citrate, 0.1˜1% of dextran 40, 3˜8% of glycerol and 0.01˜0.1% of sodium hydrogen sulfite in addition to water-soluble aluminum compound and tannic acid.

[0022] (8) The medical composition kit for treating rectal submucous lesioned abnormal tissue according to the above-mentioned (3), wherein each of the preparation for local injection and the local anesthetic is charged in a preservation container under an inert gas atmosphere.

[0023] (9) The medical composition kit for treating rectal submucous lesioned abnormal tissue according to the above-mentioned (3), wherein the container of the kit is a type where two chambers are united.

[0024] (10) The medical composition kit for treating rectal submucous lesioned abnormal tissue according to the above-mentioned (3), wherein the container of the kit is not permeable to oxygen.

[0025] (11) The medical composition kit for treating rectal submucous lesioned abnormal tissue according to the above-mentioned (3), wherein the container of the kit has a two-layered structure comprising outer and inner layers and a deoxidizer is sealed between the inner and outer layers.

[0026] (12) The medical composition kit for treating rectal submucous lesioned abnormal tissue according to the above-mentioned (3), wherein the container of the kit is a container for injection for preservation.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027]FIG. 1 is a drawing which shows the incarnation action of the medical composition kit of the present invention in terms of weight of the granulation. The data show mean value±standard error of 8 examples for each group and, in the drawing, N. S. stands for “not significant difference”.

[0028]FIG. 2 is a drawing which shows the changes in aluminum concentration in serum after administration of the medical composition kit of the present invention. The data show mean value±standard error of 5 examples for each group.

BEST MODE FOR CARRYING OUT THE INVENTION

[0029] Examples of the water-soluble aluminum compound in the present invention are aluminum chloride, aluminum sulfate, aluminum carbonate, aluminum acetate, aluminum nitrate, aluminum lactate, aluminum tartrate, aluminum salicylate, aluminum sodium sulfate, aluminum potassium sulfate, aluminum cesium sulfate and aluminum ammonium sulfate. Those water-soluble aluminum compounds may be used either solely, or two or more thereof may be used jointly. Particularly optimum one among them is aluminum potassium sulfate. Its action is that blood flow of hemorrhoid tissue is blocked whereby hemostatic action is achieved quickly and hemorrhoid is degenerated. In addition, hemorrhoid interstitium tissue is fibrosed via an aseptic inflammation inducing action and mucosa and submucous layer of hemorrhoid (including overextended blood vessel and sustentaculum) are fused and fixed to muscle layer whereupon hemorrhoid is sclerosed and degenerated.

[0030] It is preferred that the above-mentioned water-soluble aluminum compound during the fractional charging is 0.01 to 0.5 molar concentration or, preferably, 0.03 to 0.3 molar concentration. Effective concentration in the fractionally charged preparation is within a range of about 1% to about 10%, preferably about 2% to about 5% or, more preferably, about 4%. The said fractionally charged preparation is one of the two constitutions of the medical composition kit of the present invention and its preparation is carried out in such a manner that the final concentration of the water-soluble aluminum compound in the mixed final preparation is made about 2%.

[0031] With regard to tannic acid in the present invention, those derived from various plants, etc. may be used and that derived from gallnut is particularly preferred. This tannic acid plays a role that it does not suppress the tissue sclerosing action of the water-soluble aluminum compound but reduces an excessive acute inflammation reaction having a possibility of causing tissue disorder. During the fractional charging, it is compounded together with the water-soluble aluminum compound and its contained ratio in terms of effective concentration in the fractionally charged preparation is within a range of 0.01% to 2%, preferably, 0.0-5% to 1.5% and, more preferably, about 0.15%. The said concentration is adjusted in such a manner that the final concentration of tannic acid in the mixed final preparation is about 0.075%. Incidentally, tannic acid may be added in more amount than the above range provided that amount of other components, particularly sodium hydrogen sulfite, is adjusted but, in that case, coloration and precipitation are apt to occur when the prepared composition is preserved for a long term and utmost carefulness is to be paid for preparation and preservation whereby that is inconvenient.

[0032] In the fractionally charged preparation containing the water-soluble aluminum compound, a chelating agent such as sodium citrate is added so that the metal ion of a small amount existing in the solution is trapped and, at the same time, stabilization of the water-soluble aluminum compound is attempted. Its adding amount in the fractionally charged preparation to the amount of the water-soluble aluminum compound is within a range of about 10% to about 80% or, preferably, about 20% to about 50% although that may be appropriately modified depending upon the type, adding amount, etc. of the water-soluble aluminum compound. The preferred adding concentration is about 1.5% and is adjusted so as to make the final concentration 0.75% after mixing. Incidentally, addition of the chelating agent is carried out by adding to a solution containing the water-soluble aluminum compound before compounding tannic acid with the water-soluble aluminum compound.

[0033] In addition, tannic acid is unstable to light and to air even in its solid state and, therefore, it is believed to be more unstable in a solution in view of diffusion velocity among the reaction substances. Therefore, with an object of preventing the oxidation of tannic acid, an antioxidant such as sodium hydrogen sulfite is added. In the present invention, the contained ratio of sodium hydrogen sulfite used as an antioxidant is usually about 50% to about 200% or, preferably, about 70% to about 150% to tannic acid. The preferred adding concentration in the fractionally charged preparation is about 0.15% and is adjusted so as to make the final concentration about 0.075% after mixing.

[0034] In order to further stabilize the fractionally charged preparation containing the water-soluble aluminum compound as such, it is also possible that polyhydric alcohol and/or saccharide which are/is generally added to a composition for the treatment of hemorrhoid are/is added to the above composition if necessary. Examples of such polyhydric alcohol and saccharide are glycerol, glucose, fructose, xylitol, mannose, mannitol, galactose and dextran. Dextran is particularly useful for adjusting the viscosity of the preparation. Such polyhydric alcohol and saccharide may be used solely, or two or more thereof may be used jointly by mixing them. With regard to the contained rate of such polyhydric alcohol and/or saccharide, although there is no particular limitation provided that the osmotic pressure as compared with a physiological saline is about 3- to about 15-fold or, preferably, about 4- to about 8-fold, it is preferably contained within a range of about 3% to about 20% or, preferably, about 5% to about 15% in terms of an effective concentration in the preparation. Preferred adding concentration in the fractionally charged preparation is about 0.7% of dextran such as dextran 40 and about 10% of glycerol and it is prepared so as to make their final concentrations about 0.35% and about 5%, respectively after mixing.

[0035] The fractionally charged preparation containing the water-soluble aluminum compound in accordance with the present invention is constituted from a composition which is substantially composed of water-soluble aluminum compound, tannic acid, chelating agent and sodium hydrogen sulfite and the pH is adjusted to 1.0˜3.5 or, preferably, 2˜3. If necessary, pharmacologically nontoxic acid or alkali which is commonly used for the manufacture of the preparation may be used for adjusting the pH of the fractionally charged preparation containing the water-soluble aluminum compound of the present invention to an extent of the above-mentioned range. For the adjustment of the pH as such, it is possible to use a mineral acid such as hydrochloric acid or sulfuric acid, sodium hydrogen carbonate, sodium hydroxide, etc. As a result of controlling the pH of the resulting preparation within the above-mentioned range, the said preparation does not result in coloration or precipitation during the preservation for a long period and is quite stable and that is preferred. A preparing method whereby the above-mentioned pH is maintained even after mixing the preparation for treatment with the local anesthetic is preferred.

[0036] Method for the manufacture of the fractionally charged preparation containing a water-soluble aluminum compound in accordance with the present invention is as follows. Thus, all components except tannic acid are compounded with sodium hydrogen sulfite in any order and tannic acid is finally compounded therewith or a compounded product obtained by compounding a water-soluble aluminum compound with a chelating agent and another compounded product obtained by compounding tannic acid with sodium hydrogen sulfite are separately prepared, those compounds are then mixed and, if necessary, polyhydric alcohol and/or saccharide are/is added to each of or one of the above compounded products or to a mixture of the said compounded products. When the components are compounded as such, oxidation of tannic acid can be prevented and, in addition, direct reaction of tannic acid with metal ion such as aluminum ion derived from aluminum potassium sulfate can be prevented whereupon a stable preparation for fractional charge where the composition is constant containing water-soluble aluminum compound and tannic acid can be prepared.

[0037] As a kit constitution, the medical composition kit for treating rectal submucous lesioned abnormal tissue according to the present invention is constituted from the above-mentioned local injection preparation for treating rectal submucous lesioned abnormal tissue (a fractionally preserved preparation containing a water-soluble aluminum compound) containing a water-soluble aluminum compound and tannic acid and lidocaine hydrochloride injection or procaine hydrochloride injection as local anesthetic. Lidocaine hydrochloride and procaine hydrochloride injection are the anesthetics which have been already and well known in Japan and they are selected in the present invention due to the reason that they have less toxic phenomena of anaphylaxis as compared with other known local anesthetics. More preferably, lidocaine hydrochloride injection is used. When the influence of the local anesthetic on incarnation action of the preparation containing the water-soluble aluminum compound and on the fate of drug of aluminum was investigated, both lidocaine hydrochloride injection and procaine hydrochloride injection showed no particular influence. Its concentration in the preparation for fractional charging is 0.1˜1% or, preferably, about 0.5% in the case of lidocaine hydrochloride injection. It is prepared so as to make the concentration 0.05˜0.5% or, preferably, about 0.25% after mixing. With regard to lidocaine hydrochloride, there are also appropriately utilized lidocaine hydrochloride-epinephrine, lidocaine hydrochloride-epinephrine bitartrate and lidocaine hydrochloride-1-norepinephrine. In the case of procaine hydrochloride injection, the concentration is 0.5˜5% or, preferably, about 1%. It is prepared so as to make the concentration 0.1˜1% or, preferably, about 0.5% after mixing.

[0038] Each of the preparations for fractional charging prepared as such is made into a form of kit in a fractionally charged form (fractionally preserved preparation) for each dose for one application and both preparations are used by mixing in actual use. Fractional charging is previously carried out in such a manner that, when mixed, final concentration in the final preparation of water-soluble aluminum compound is about 2%, that of tannic acid is about 0.075% and that of lidocaine hydrochloride or procaine hydrochloride is about 0.25% or about 0.5%, respectively. Each of the preparations for fractional charging is fractionally charged in 2.5˜30 mL or, preferably, about 5˜20 mL and both preparations are used by mixing in actual use.

[0039] With regard to the container for charging the preparation of each fractionally charging preparation of a medical composition kit for treating rectal submucous lesioned abnormal tissue in accordance with the present invention, there may be used bag, plastic container, ampoule, vial or glass container. The container may be that having an object of mere preservation or may be an injection container for preservation (a pre-filled syringe type). In a method for the manufacture of preparation charged in injection container for preservation, each or any of the components constituting the above-mentioned preparations for fractionally charging is manufactured under an atmosphere of inert gas (under such a condition that oxygen in the atmosphere or in the using water is substantially absent or is only in a limited amount having no bad affection to the resulting composition). With regard to the inert gas, nitrogen gas may be exemplified.

[0040] The preparation for fractional charging according to the present invention manufactured as such is charged in a container after conventional aseptic filtration, then subjected to high-pressure steam sterilization if necessary and preserved at room temperature. This charging process is also preferred to be carried out under the atmosphere of inert gas such as nitrogen gas. Usually, oxygen dissolved in the preparation for injection is deaerated by a conventional method and then substitution with nitrogen is conducted by introducing nitrogen gas thereinto.

[0041] It is also possible that the injection preparation which is a fractionally charged preparation according to the present invention is subjected to freeze-drying by a conventional manner to prepare into a kit together with a dissolving agent whereby it is used by dissolving in actual use. With regard to a dissolving liquid for the preparation in actual use, it is possible to use a solution where polyhydric alcohol and/or saccharide are/is dissolved.

[0042] In a medical composition kit for treating rectal submucous lesioned abnormal tissue of the present invention, a charging container for a preparation for local injection containing water-soluble aluminum compound and a local anesthetic is constituted in a two-chamber container in a united type and it may be a container where the partition between the two chambers is released in actual use whereby mixing is possible or may be separate containers and mixing is conducted in actual use although the former is more convenient. A two-chamber container in a united type is commonly used in case the substances which need a fractional preservation are mixed and such a one may be utilized.

[0043] Further, it is preferred that the container used for the kit of the present invention is not permeable to oxygen. In addition, it is appropriate for the preservation of the charged preparation to use a container having a two-layered structure comprising outer and inner layers where a deoxidizer is sealed between the inner and outer layers.

[0044] The preparation for local injection containing a water-soluble aluminum compound and the local anesthetic of the a medical composition kit for treating rectal submucous lesioned abnormal tissue according to the present invention provided as such are mixed in actual use, have a fibrosing action for administering sites of digestive organs particularly large intestine and rectum and are able to sclerose and degenerate the lesioned tissue by contacting with lesioned tissue such as that suffering from internal hemorrhoid or rectal prolapse and lesioned tissue such as protruded lesioned tissue whereby it is a preparation achieving excellent convenience and certainty in actual use.

EXAMPLES

[0045] The present invention will now be illustrated in detail by way of the following Examples and Experimental Examples.

Example 1

[0046] Components of the treating preparation and the local anesthetic contained in the kit and their manufacturing methods are as follows.

[0047] a. Treating Preparation

[0048] Aluminum potassium sulfate (400 mg), 150 mg of sodium citrate, 15 mg of sodium hydrogen sulfite, 15 mg of tannic acid, 70 mg of dextran 40, 1000 mg of glycerol and an appropriate amount of distilled water for injection were used to make the total volume 10 mL. This preparation is called OC-108.

[0049] Each component was weighed to give the above compounding and the treating preparation was prepared by the following manufacturing method.

[0050] Firstly, water for injection satisfying the regulation of the Japanese Pharmacopoeia was heated at 100° C. for 5 minutes to remove the dissolved oxygen. After finishing the heating, it was allowed to cool at room temperature together with introduction of nitrogen gas. Since dextran 40 is hardly soluble in water, it was separately and previously dissolved in water for injection completely and the resulting solution was used. After that, sodium hydrogen sulfite was dissolved in an appropriate amount of water for injection, then a dextran 40 solution, sodium citrate, aluminum potassium sulfate and glycerol were added to the resulting solution and, after that, tannic acid was added whereupon each component was dissolved. During the dissolving step, nitrogen gas was introduced into the solution. The resulting solution was then stirred for about 30 minutes and filtered using a filter. Nitrogen gas was continuously introduced to the filtered solution to give the aimed composition. The pH of this composition was 2.7. Each 10 mL of the composition were charged into a vial or an ampoule. During the charging, pre-substitution and post-substitution with nitrogen gas were carried out and the said container was tightly sealed and preserved at room temperature. The resulting liquid was colorless to pale yellow and clear being slightly viscous. Under an accelerated preservation test condition at 40° C., it was stable for six months. As a result, it was found that this was stable for three years at room temperature. It was stable to light as well.

[0051] b. Local Anesthetic

[0052] To lidocaine (Japanese Pharmacopoeia) was added the corresponding amount of hydrochloric acid to prepare a 0.5% lidocaine hydrochloride injection according to the known method for the manufacture of injection preparations, then a preservative such as methyl p-hydroxybenzoate or butyl p-hydroxybenzoate was added thereto and each 10 mL thereof were charged into a vial or an ampoule under the nitrogen gas atmosphere followed by sealing tightly.

[0053] c. Medical Composition Kit for Treating Rectal Submucous Lesioned Abnormal Tissue

[0054] There was prepared a medical composition kit for treating rectal submucous lesioned abnormal tissue comprising a fractionally charging preparation containing 10 mL of 0.5% lidocaine hydrochloride injection and a fractionally charging preparation containing 10 mL of local injection solution containing aluminum potassium sulfate.

Example 2

[0055] The same operation as in Example 1 was carried out except that 1% procaine hydrochloride injection was used instead of 0.5% lidocaine hydrochloride injection to prepare a medical composition kit for treating rectal submucous lesioned abnormal tissue comprising a fractionally charging preservation preparation containing 10 mL of 1% procaine hydrochloride injection and a fractionally charging preservation preparation containing 10 mL of local injection solution containing aluminum potassium sulfate.

Experimental Example 1

[0056] The kit prepared in Example 1 and the kit prepared in Example 2 were used to manufacture each mixed preparation. The amount of the water-soluble aluminum compound in each of the mixed preparations was 2%. As a control, there was prepared a preparation where the amount of the water-soluble aluminum compound was made 2% using a physiological saline (10 mL) instead of the local anesthetic in each kit. An air pouch was formed under the skin of the back of a male rat, the air in the said pouch was removed after 2 days, 2 mL of the above-prepared test solution were administered to the said site, granulation tissue grown on the pouch site was excised after 14 days from the administration and its weight was measured. The result is as shown in FIG. 1 and, in any of the prepared solutions, there was a granulation forming action in the same degree and the influence by the local anesthetic was not noted.

[0057] As another experimental system, the same preparation as above was prepared and subcutaneously administered to a male rat in a dose of 20 mg/kg as aluminum potassium sulfate and changes in the concentration of aluminum in serum was measured. Incidentally, the measured value was expressed in terms of aluminum concentration where the value in serum of a rat to which nothing was administered was deducted. The result is as shown in FIG. 2 and any of the prepared solutions showed the same changes in aluminum concentration in serum where there was no significant influence by local anesthetic.

Experimental Example 2

[0058] The kit prepared in Example 2 was used and the mixed preparation was directly administered into hemorrhoid of the patients suffering from internal hemorrhoid in a severe state of internal hemorrhoid of degrees III and IV according to the internal hemorrhoid classification by Goligher and fate of the drug, efficacy and safety were investigated. The analyzed cases were 15.

[0059] a. Efficacy

[0060] After 28 days from the administration, investigations were conducted for degree of improvement in prolapse, bleeding and hemorrhoid size which were main evaluating items and, as a result, improvements of not lower than medium degree were 100%, 92% and 100%, respectively. No prolapse was noted in all cases and most of hemorrhoid was also sclerosed and degenerated in all cases.

[0061] b. Safety

[0062] With regard to the safety as a whole, “safe” was 80%. As to the side effect, hematuria, pollakisuria and polyuria were noted in one of 15 cases as subjective and objective symptoms. There was no complaint of pain during and after the administration of injection solution, sense of discomfort at anus and uncomfortable feeling at anus in all cases.

[0063] c. Fate of Drug of Aluminum

[0064] Total dose to the object to be analyzed was 27˜42 mL and the time for administration was 4˜17 minutes. Concentration in serum after administration and excreted rate into urine were expressed by deducting the values before administration in each case. Aluminum concentration in serum before administration was less than the limit for quantification (0.01 μg/mL) in all cases. When 8.4˜13.7 mg/kg as aluminum potassium sulfate in the mixed preparation were administered into hemorrhoid, the level reached C_(max)(1.80±0.51 μg/mL) after 0.71±0.37 hour from completion of administration and then, in the final phase, it disappeared with a half-life of 149.3±170.7 hours. AUC_(0-24 h) and AUC₀₋₄ were 13.8±3.7 and 38.7±14.7 μg/mL, respectively. A dose correlation was noted between the dose (mg/kg) and the values of C_(max) and AUC_(0-24 h). Excreted rate of aluminum into urine until 96 hours after the administration was 56.6±11.1%.

[0065] d. Conclusion

[0066] It has been noted from the above that the medical composition kit in accordance with the present invention is a very effective preparation for internal hemorrhoid in a severe degree and that both safety and painlessness are guaranteed.

Industrial Applicability

[0067] As illustrated hereinabove, investigations on selection and compounding ratio of use of the local anesthetic were carried out in a preparation of local injection for treating rectal submucous lesioned abnormal tissue containing a water-soluble aluminum compound and tannic acid whereupon it was found that lidocaine hydrochloride or procaine hydrochloride injection, particularly lidocaine hydrochloride injection, was able to be used therewith as a very useful local anesthetic. When they are previously made into a medical composition kit, the precision of the compounding ratio can be maintained and, in addition, a preparation where safety and painlessness are guaranteed can be provided. Further, the present invention is able to avoid the troublesomeness of medical doctors in the therapy and is of much convenience. 

1. In a composition kit for the treatment where respective containers are unsealed upon being used and respective contents are mixed to obtain a preparation for injection, a medical composition kit for treating rectal submucous lesioned abnormal tissue which is characterized in that respective single doses of a therapeutic preparation and local anesthetic are fractionally charged in containers, the said therapeutic preparation contains 1˜10% of a water-soluble aluminum compound and 0.01˜2% of tannic acid and the said local anesthetic contains 0.1˜1% of lidocaine hydrochloride.
 2. In a composition kit for the treatment where respective containers are unsealed upon being used and respective contents are mixed to obtain a preparation for injection, a medical composition kit for treating rectal submucous lesioned abnormal tissue which is characterized in that respective single doses of a therapeutic preparation and local anesthetic are fractionally charged in containers, the said therapeutic preparation contains 1˜10% of a water-soluble aluminum compound and 0.01˜2% of tannic acid and the said local anesthetic contains 0.5˜5% of procaine hydrochloride.
 3. The medical composition kit for treating rectal submucous lesioned abnormal tissue according to claim 1 or 2, wherein the water-soluble aluminum compound, tannic acid and lidocaine hydrochloride or procaine hydrochloride are previously and fractionally charged so that the final concentrations of them in the final preparation prepared as an injection preparation by mixing them are made 1.5˜2.5%, 0.01˜0.1% and 0.05˜0.5% or 0.1˜1%, respectively.
 4. The medical composition kit for treating rectal submucous lesioned abnormal tissue according to claim 3, wherein pH of the preparation for the treatment is 2˜3.
 5. The medical composition kit for treating rectal submucous lesioned abnormal tissue according to claim 3, wherein the water-soluble aluminum compound is aluminum potassium sulfate.
 6. The medical composition kit for treating rectal submucous lesioned abnormal tissue according to claim 3, wherein the preparation for the treatment contains a chelating agent and an additive for stabilization.
 7. The medical composition kit for treating rectal submucous lesioned abnormal tissue according to claim 6, wherein the final preparation where each component is mixed to give an injection preparation is prepared so as to contain 0.5˜1% of sodium citrate, 0.1˜1% of dextran 40, 3˜8% of glycerol and 0.01˜0.1% of sodium hydrogen sulfite in addition to water-soluble aluminum compound and tannic acid.
 8. The medical composition kit for treating rectal submucous lesioned abnormal tissue according to claim 3, wherein each of the preparation for local injection and the local anesthetic is charged in a preservation container under an inert gas atmosphere.
 9. The medical composition kit for treating rectal submucous lesioned abnormal tissue according to claim 3, wherein the container of the kit is a type where two chambers are united.
 10. The medical composition kit for treating rectal submucous lesioned abnormal tissue according to claim 3, wherein the container of the kit is not permeable to oxygen.
 11. The medical composition kit for treating rectal submucous lesioned abnormal tissue according to claim 3, wherein the container of the kit has a two-layered structure comprising outer and inner layers and a deoxidizer is sealed between the inner and outer layers.
 12. The medical composition kit for treating rectal submucous lesioned abnormal tissue according to claim 3, wherein the container of the kit is a container for injection for preservation. 